p53-Related Transcription Targets of TAp73 in Cancer Cells—Bona Fide or Distorted Reality?

Abstract

Identification of p73 as a structural homolog of p53 fueled early studies aimed at determining if it was capable of performing p53-like functions. This led to a conundrum as p73 was discovered to be hardly mutated in cancers, and yet, TAp73, the full-length form, was found capable of performing p53-like functions, including transactivation of many p53 target genes in cancer cell lines. Generation of mice lacking p73/TAp73 revealed a plethora of developmental defects, with very limited spontaneous tumors arising only at a later stage. Concurrently, novel TAp73 target genes involved in cellular growth promotion that are not regulated by p53 were identified, mooting the possibility that TAp73 may have diametrically opposite functions to p53 in tumorigenesis. We have therefore comprehensively evaluated the TAp73 target genes identified and validated in human cancer cell lines, to examine their contextual relevance. Data from focused studies aimed at appraising if p53 targets are also regulated by TAp73—often by TAp73 overexpression in cell lines with non-functional p53—were affirmative. However, genome-wide and phenotype-based studies led to the identification of TAp73-regulated genes involved in cellular survival and thus, tumor promotion. Our analyses therefore suggest that TAp73 may not necessarily be p53’s natural substitute in enforcing tumor suppression. It has likely evolved to perform unique functions in regulating developmental processes and promoting cellular growth through entirely different sets of target genes that are not common to, and cannot be substituted by p53. The p53-related targets initially reported to be regulated by TAp73 may therefore represent an experimental possibility rather than the reality.

p73 as a Tissue Architect

“…The complex phenotype of the Trp73 deficient mice have revealed that p73 function is essential for the organization and homeostasis of different complex microenvironments governing various aspects of tissue physiology. Altogether, this has raised the idea that TAp73 was not evolved for tumor suppression, but rather to perform unique functions in regulating developmental processes through p53-independent mechanisms (Wang et al, 2020). We propose that some of the, apparently unrelated, phenotypes observed in Trp73 −/− mice are the reflection of the p73 requirement for the establishment and/or maintenance of tissue organization (Figure 4).…”

“…The discovery of the TA-and DN-p73 isoforms with antagonist anti-and pro-oncogenic functions, and the TAp73KO mice predisposition to spontaneous tumorigenesis, demonstrated TAp73 role as a tumor suppressor gene (Tomasini et al, 2008). However, there is growing evidence indicating that while TAp73 has a role in tumor suppression, it is likely to be secondary (reviewed in Wang et al, 2020). The complex phenotype of the Trp73 deficient mice have revealed that p73 function is essential for the organization and homeostasis of different complex microenvironments governing various aspects of tissue physiology.…”

“…As mentioned before, the Trp73 gene gives raise to functionally different TA and DNp73 isoforms (Candi et al, 2014). TAp73 proteins can transactivate canonical-p53 targets as well as non-p53 related genes involved in development and/or other cell growth associated functions (Engelmann et al, 2015;Wang et al, 2020). TA-isoforms differ in their transactivation efficiency and target gene specificity depending on their carboxy terminus (De Laurenzi et al, 1998;Ueda et al, 1999).…”

The foggy world(s) of p63 isoform regulation in normal cells and cancer

“…Clinically, p63 has value in identifying malignancy and for tumour classification, and isoform‐specific ΔNp63 antibodies are superior to assessing total p63 in many situations (reviewed in ref 249). In addition, although not well studied in clinical material, TAp63 provides prognostic information [15,18,249–251] and requires more study in lymphomas and lymphocytes (including tumour‐infiltrating lymphocytes) to understand its prognostic impact and opportunities for therapy. Advances in understanding p63 isoforms and their regulation will inevitably lead to new diagnostic, prognostic and therapeutic opportunities for cancer and other pathological conditions.…”

Mechanisms of Functional Pleiotropy of p73 in Cancer and Beyond

“…Besides their well-demonstrated roles in DDR and apoptosis ( Wilhelm et al, 2010 ), p73 isoforms also have unique targets ( Logotheti et al, 2019 ; Wang et al, 2020 ) and exert non-oncogenic functions ( Inoue et al, 2014 ) that are not shared with p53. Understanding their functional pleiotropy has been enabled through the use of DNp73 splice isoform-specific antisense oligonucleotide gapmers ( Emmrich et al, 2009 ) and by knockout mice models with (i) deletion of the entire TP73 gene, (ii) deletion of exons encoding the TAp73 isoforms, (iii) deletion of exons encoding the ΔNp73 isoform, and (iv) deletions of exons encoding the C-terminus of the alpha isoform.…”